U.S. patent application number 14/446906 was filed with the patent office on 2015-02-05 for administration of a therapeutic amount of genistein to mitigate erectile dysfunction resulting from radiation therapy for prostate cancer only throughout a defined administration period commencing shortly before and concluding after radiation therapy.
The applicant listed for this patent is Humanetics Corporation. Invention is credited to Michael D. Kaytor, Geoffrey E. Schroeder, John L. Zenk.
Application Number | 20150038572 14/446906 |
Document ID | / |
Family ID | 51260715 |
Filed Date | 2015-02-05 |
United States Patent
Application |
20150038572 |
Kind Code |
A1 |
Kaytor; Michael D. ; et
al. |
February 5, 2015 |
ADMINISTRATION OF A THERAPEUTIC AMOUNT OF GENISTEIN TO MITIGATE
ERECTILE DYSFUNCTION RESULTING FROM RADIATION THERAPY FOR PROSTATE
CANCER ONLY THROUGHOUT A DEFINED ADMINISTRATION PERIOD COMMENCING
SHORTLY BEFORE AND CONCLUDING AFTER RADIATION THERAPY
Abstract
A method for mitigating erectile dysfunction as an adverse side
effect of radiation therapy for prostate cancer, comprising
administration of a therapeutic dosage of genistein to a patient
diagnosed with prostate cancer throughout only a primary
administration period that commences a defined period of up to two
weeks prior to commencement of radiation therapy for prostate
cancer and extends beyond conclusion of the radiation therapy.
Inventors: |
Kaytor; Michael D.;
(Maplewood, MN) ; Zenk; John L.; (Eden Prairie,
MN) ; Schroeder; Geoffrey E.; (Woodbury, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Humanetics Corporation |
Minneapolis |
MN |
US |
|
|
Family ID: |
51260715 |
Appl. No.: |
14/446906 |
Filed: |
July 30, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61861642 |
Aug 2, 2013 |
|
|
|
Current U.S.
Class: |
514/456 |
Current CPC
Class: |
A61K 9/006 20130101;
A61P 15/10 20180101; A61K 31/353 20130101; A61K 31/352
20130101 |
Class at
Publication: |
514/456 |
International
Class: |
A61K 31/353 20060101
A61K031/353; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method for mitigation of erectile dysfunction as an adverse
side effect of radiation therapy for prostate cancer, comprising
administration of a therapeutic dosage of genistein to a patient
diagnosed with prostate cancer throughout only a primary
administration period that commences a defined period of up to two
weeks prior to commencement of radiation therapy for prostate
cancer and extends beyond conclusion of the radiation therapy.
2. The method of claim 1 wherein the primary administration period
commences at least one week prior to commencement of radiation
therapy for prostate cancer.
3. The method of claim 1 wherein the primary administration period
commences at least three days prior to commencement of radiation
therapy for prostate cancer.
4. The method of claim 1 wherein the primary administration period
continues for at least one month after completion of radiation
therapy for prostate cancer.
5. The method of claim 1 wherein the primary administration period
continues for at least two months after completion of radiation
therapy for prostate cancer.
6. The method of claim 1 wherein the primary administration period
continues for at least three months after completion of radiation
therapy for prostate cancer.
7. The method of claim 1 wherein the primary administration period
continues for at least six months after completion of radiation
therapy for prostate cancer.
8. The method of claim 1 wherein a maintenance dosage of less than
60% the amount of the therapeutic dosage is administered during a
maintenance period after completion of the primary administration
period.
9. The method of claim 8 wherein the maintenance period is at least
one month.
10. The method of claim 8 wherein the maintenance period is at
least three months.
11. The method of claim 8 wherein the maintenance period is at
least six months.
12. The method of claim 1 wherein a maintenance dosage is
administered during a maintenance period after completion of the
primary administration period, and wherein the maintenance dosage
is administered at a frequency that is one-half or less of the
frequency at which the therapeutic dose was administered.
13. The method of claim 1 wherein a maintenance dosage is
administered during a maintenance period after completion of the
primary administration period, and wherein the maintenance dosage
is administered at a frequency that is one-quarter or less of the
frequency at which the therapeutic dose was administered.
14. The method of claim 12 wherein the maintenance period is at
least one month.
15. The method of claim 13 wherein the maintenance period is at
least three months.
16. The method of claim 12 wherein the maintenance period is at
least six months.
17. The method of claim 1 wherein the genistein is administered in
the form of a nanosuspension.
18. The method of claim 1 comprising administration of at least 1
gram per day of genistein.
19. The method of claim 1 comprising administration of at least 1.2
grams per day of genistein.
20. The method of claim 1 comprising administration of at least 1.5
grams per day of genistein.
21. The method of claim 1 wherein administration is effected
orally.
Description
FIELD OF INVENTION
[0001] The invention relates to methods of mitigating erectile
dysfunction as an adverse side effect of radiation therapy for
prostate cancer.
BACKGROUND
[0002] The most common type of cancer in the United States is
prostate cancer. The United States National Cancer Institute
estimates that more than 238,000 new cases will occur in the United
States in 2013. Although the incidence is high, so is the survival
rate. Treatment options for localized prostate cancer include
radiation therapy, radical prostatectomy, hormone therapy, and
combinations thereof. External beam radiation is one of the more
commonly used treatment options. One of the adverse side effects of
radiation treatment for prostate cancer is erectile dysfunction,
resulting from radiative collateral damage to the penis and penile
bulb. The resultant erectile dysfunction may and often does have a
significant impact on a patient's quality of life. Accordingly, a
substantial need exists for a treatment regimen capable of reducing
the severity and/or incidence of erectile dysfunction following
radiation therapy for prostate cancer.
[0003] One study, self-acknowledged as suffering from a number of
weaknesses that limit the value of the resultant data, including an
insufficient number of subjects, an insufficient number of adverse
events, an insufficient percentage of participants completing the
program, and reliance upon participant self-evaluation and
self-reporting, found that administration of 200 mg/day of soy
isoflavone, containing a ratio of 1.1:1:0.2
genistein:daidzein:glycitein, during and after radiation therapy
for prostate cancer, had the potential to ameliorate radiation
toxicity, including the adverse side effect of erectile
dysfunction. Ahmad, I., Forman, J., Sarkar, F., Hillman, G., Heath,
E., Vaishampayan, U., Cher, M., Andic, F., Rossi, P., and Kucuk,
O., (2010) Soy Isoflavones in Conjunction With Radiation Therapy in
Patients With Prostate Cancer Nutrition and Cancer, 62(7),
996-1000. Other clinical trials found no beneficial effects of
genistein or soy isoflavones.
[0004] The treatment regimen disclosed in the Ahmad et al. article
inadequately mitigates the adverse side effect of erectile
dysfunction following radiation therapy for prostate cancer.
[0005] Hence, a substantial need continues to exist for a method of
mitigating the sexual adverse effect of erectile dysfunction
associated with radiation therapy for prostate cancer.
SUMMARY OF THE INVENTION
[0006] The invention is directed to a method for mitigating
erectile dysfunction as an adverse side effect of radiation therapy
for prostate cancer, comprising administration of a therapeutic
dosage of genistein to a patient diagnosed with prostate cancer
throughout only a primary administration period that commences a
defined period of up to two weeks prior to commencement of
radiation therapy for prostate cancer and extends beyond conclusion
of the radiation therapy.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
Theory
[0007] Chronic oxidative stress is a major indirect cause of
radiation-induced injury to cellular macromolecules, leading to DNA
damage, cell death, and persistent activation/inactivation of
signaling molecules involved in vascular function and inflammation,
thus resulting in aberrant wound healing. Oxidative stress in
penile tissue plays a crucial role in the development of radiation
therapy induced erectile dysfunction via activation of NADPH
oxidase, which leads to development of chronic oxidative stress
followed by persistent inflammation. NADPH-oxidase-derived reactive
oxygen species are a major source of oxidative stress after
radiation. Vascular NADPH oxidases produce superoxide anions or
hydrogen peroxide molecules that impede the ability of
endothelial-derived nitric oxide (NO) to cause vasodilation, both
through reducing the bioavailability of NO and inhibiting
components of its signaling pathway. This results in
vasoconstriction, reduced blood flow to the tissue, and subsequent
erectile dysfunction. Without intending to be limited thereby, it
is believed that genistein's ability to mitigate the sexual adverse
effect of erectile dysfunction associated with radiation therapy
for prostate cancer is mediated via genistein's anti-inflammatory
properties and its ability, when administered in therapeutically
sufficient dosage, to scavenge the reactive oxygen species
responsible for the cellular damage that results in erectile
dysfunction.
DESCRIPTION
[0008] Administration of a therapeutically effective dosage of
genistein to a patient diagnosed with prostate cancer during only a
primary administration period that commences a defined period of up
to two weeks prior to commencement of radiation therapy for
prostate cancer and extends beyond conclusion of the radiation
therapy, can mitigate the adverse side effect of erectile
dysfunction associated with such radiation therapy.
[0009] Commencing administration of genistein more than two weeks
prior to commencement of radiation therapy for prostate cancer
increases the cost of the therapy in the absence of a concomitant
enhancement in mitigation of radiation therapy induced erectile
dysfunction and unnecessarily delays commencement of radiation
therapy, in the absence of a concomitant enhancement in mitigation
of radiation therapy induced erectile dysfunction.
The Active Agent
[0010] Genistein belongs to the pharmacological classes of soy
isoflavone, flavonoid, polyphenol and phytoestrogen. It is also
known as 5,7-dihydroxy-3-(4-hydroxyphenyl)-chromen-4-one (IUPAC),
5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one,
5,7,4'-trihydroxyisoflavone, 4',5,7-trihydroxyisoflavone,
Genestein, Prunetol, Sophoricol and Differenol A. It has a
Molecular Formula of C.sub.15H.sub.10O.sub.5, a Molecular Weight of
270.237 g/mol (270.24 daltons), a Chemical Abstracts Service (CAS)
Registry Number 446-72-0 and a Beilstein Registry Number 263823. It
is commercially available from a number of sources, including DSM
Nutritional Products, Inc. of Basel, Switzerland under Drug Master
File (DMF) #19747-PIND #104,709.
Administration
Administration Route
[0011] Genistein can be administered by virtually any of the
commonly accepted practices for the administration of
pharmaceutical preparations including specifically, but not
exclusively, mucosal administration, oral consumption, ocular
administration, subcutaneous injection, transdermal administration,
intravascular administration, intramuscular administration, etc.
Oral administration is generally preferred.
[0012] Mucosal administration of genistein includes such routes as
buccal, endotracheal, nasal, pharyngeal, rectal, sublingual,
vaginal, etc. For administration through the
buccal/sublingual/pharyngeal/endotracheal mucosal, genistein may be
formulated as an emulsion, gum, lozenge, spray, tablet or an
inclusion complex such as cyclodextrin inclusion complexes. Nasal
administration is conveniently conducted through the use of a
sniffing powder or nasal spray. For rectal and vaginal
administration, genistein may be formulated as a cream, douche,
enema or suppository.
[0013] Oral consumption of genistein may be effected by
incorporating the genistein into a food or drink, or formulating
the genistein into a chewable or swallowable tablet or capsule. The
genistein is preferably orally administered as a nanosuspension in
accordance with U.S. Patent Application Publications 2012/0164190
and 2012/0121654, both hereby incorporated by reference.
[0014] Genistein is virtually insoluble in water, thereby limiting
its bioavailability when administered orally. Genistein provided as
a nano suspension in accordance with US Patent Application
Publications 2012/0164190 and 2012/0121654 has significantly
improved oral bioavailability. This allows dosing without medical
supervision, which enables pre-dosing at home prior to known and
planned instances of radiation therapy. To further improve oral
bioavailability, genistein can also be incorporated as sub-micron
size particles in an orally ingestible formulation. Generally, a
dose of .about.1 g per day of genistein provided as a
nanosuspension should be effective for achieving the desired
mitigating protective effect.
[0015] Ocular administration may be effected by incorporating
genistein into a solution or suspension adapted for ocular
application such as drops or sprays.
[0016] Subcutaneous, intravascular and intramuscular administration
involves incorporating the genistein into a pharmaceutically
acceptable and injectable carrier.
[0017] For transdermal administration, the genistein may be
conveniently incorporated into a lipophilic carrier and formulated
as a topical cream or adhesive patch.
Administration Dosage and Timing
[0018] The range of dosages effective for achieving the desired
mitigation of erectile dysfunction associated with radiation
therapy of prostate cancer may be determined in accordance with
standard industry practices. The desired protective effect can
generally be achieved by administration of at least .about.1 gram
of genistein per day, preferably at least .about.1.2 grams of
genistein per day and most preferably at least .about.1.5 grams of
genistein per day, taken as a single dose or multiple doses each
day. Lower amounts may also be therapeutic.
[0019] Genistein administered for a short-term prior to
commencement of radiation therapy for prostate cancer, throughout
such therapy and after conclusion of such therapy is effective for
mitigating erectile dysfunction associated with radiation therapy
for prostate cancer. Administration of a therapeutic amount of
genistein more than two weeks prior to commencement of radiation
therapy for prostate cancer contributes little towards mitigation
of this adverse side effect and is therefore discouraged as
unnecessary.
Administration Period
[0020] The administration of genistein commences prior to
commencement of radiation therapy for prostate cancer, but no more
than two weeks prior, with a preference for commencement no more
than one week prior, most preferably no more than three days prior.
Administration continues throughout the radiation therapy and
continues after conclusion of the radiation therapy.
[0021] The primary administration of genistein should continue for
at least one month after conclusion of the radiation therapy, with
a preference for continued administration for at least two months,
most preferably at least six months. A primary administration
period that continues for a period of less than one month after
conclusion of the radiation therapy tends to result in a
precipitous decline in the percentage of treated patients
benefiting from the protective effect of such administration, while
an extended period of administration can continue to benefit the
patient.
[0022] A reduced maintenance amount of genistein may be
administered for a period after completion of the primary
administration of genistein. The reduction may be in the form of a
reduced dosage (e.g., reduced to less than 60% the amount
administered during the therapeutic stage) and/or a reduced
frequency (e.g., 1/2 or 1/4 the frequency during the therapeutic
stage). When employed, the maintenance period should last for at
least one month, preferably at least three months and most
perferably at least six months. Shorter durations tend to diminish
the benefit obtained by administration of a maintenance dosage,
while administration of some maintenance amount of genistein can
perpetually benefit the patient.
* * * * *